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Methods for Molecular Classification of BRCA-Like Breast and/or Ovarian Cancer

a technology of ovarian cancer and molecular classification, applied in the field of oncology, can solve problems such as genetic instability

Inactive Publication Date: 2017-03-02
STICHTING HET NEDERLANDS KANKER INST ANTONI VAN LEEUWENHOEK ZIEKENHUIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a gene profile, called the BRCAness profile, that can indicate the presence of a BRCA mutation in breast and ovarian cancer cells. This profile can be used to assign treatment to patients with these cancers. The invention also provides a method for comparing the level of expression of genes in a sample from a cancer patient to a reference, and typing the patient as being BRCA-like or not based on this comparison. The DNA-damage inducing treatment recommended for BRCA-like patients includes alkylating agents, platinum salts, and PARP inhibitors. The invention also describes combining the BRCAness profile with other gene expression tests to determine the metastasizing potential and molecular subtype of the cancer sample.

Problems solved by technology

In the absence of homologous recombination, alternative error-prone mechanisms such as non-homologous end joining are invoked, leading to genomic instability (Karran, 2000.

Method used

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  • Methods for Molecular Classification of BRCA-Like Breast and/or Ovarian Cancer
  • Methods for Molecular Classification of BRCA-Like Breast and/or Ovarian Cancer
  • Methods for Molecular Classification of BRCA-Like Breast and/or Ovarian Cancer

Examples

Experimental program
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Effect test

example 1

Materials and Methods

[0077]Patient Samples 128 triple negative breast cancer samples (fresh frozen) with long-term follow-up were collected from two European cancer centers. BRCA1 mutation and promoter methylation was determined by next generation sequencing and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and BRCA1-like classification by MLPA [Lips et al., 2011. Breast Cancer Research 13: R107]. In addition we collected full genome expression data for all patients and mutation data for 21 known DNA repair genes. Differential gene expression was examined between tumors that classify as BRCA1-like with no mutation or methylation for mutations or dysregulation in another gene or genes involved in DNA repair, which may be responsible for the BRCA1-like phenotype. and sporadic-like.

Gene Expression Preprocessing Methods:

i) Exploratory Biological Analysis

[0078]The RNA quality was assessed by a Bioanalyzer and samples with RIN above 5 were selected for fu...

example 2

[0096]A validation set comprising 53 samples was used to test the signature. This validation set had been hybridized on the Illumina microarray platform. The data for each sample was scaled to the same median as the test set.

[0097]Tables 3-6 are presented for both the training and the 53 validation samples. The top 3 significant results (2, 72 and 77 genes) are presented in Tables 3, 4 and 5, respectively Table 6 provides the results of other gene sets on the training and the 53 validation samples. For each set of genes, both results for the training dataset and the validation dataset are indicated.

[0098]Following this, a smaller number of genes were analyzed to see if there could be a ‘minimum set’ of genes that could still give the same significance in validation. The sensitivity for a lower number of genes remained the same (or even slightly higher), however the specificity dropped.

[0099]As this signature is also developed in FF a higher number of genes may be more appropriate to...

example 3

Methods

[0102]115 HER2 negative patients (HER2−) were considered in this analysis. The BRCAness classification was computed using the 77 gene panel BRCAness gene signature. Patients were treated with oral PARP inhibitor veliparib (ABT-888) in combination with carboplatin and chemotherapy (V / C) (71 patients), or with chemotherapy alone (44 patients).

[0103]The association between BRCAness classification and response in the V / C and control arms alone (Fisher Exact test), and relative performance between arms (biomarker×treatment interaction, likelihood ratio test) was determined using a logistic model. The BRCAness signature was assessed in the context of a subset of patients that were negative for progesterone receptor, estrogen receptor and HER2 (triple negative; TN). Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content).

Results

[0104]Of the 115 patients assessed, 56 were classified as BRCA-like using the 77 gene panel BRCAness ge...

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Abstract

The invention relates to a method of assigning treatment to a breast and / or ovarian cancer patient. More specifically, the invention relates to a method for classification of breast and / or ovarian cancer as BRCA-like or sporadic-like by determining a level of expression of a set of genes and comparing said level of expression to a reference. A patient that is classified as BRCA-like is treated with a DNA-damage inducing agent.

Description

FIELD OF THE INVENTION[0001]The invention relates to the field of oncology. More specifically, the invention relates to a method for typing breast and / or ovarian cancer cells. The invention provides means and methods for classification of breast and / or ovarian cancer cells.BACKGROUND OF THE INVENTION[0002]Maintenance of DNA integrity depends on homologous recombination, a conservative mechanism for error-free repair of double strand breaks (DSBs). In the absence of homologous recombination, alternative error-prone mechanisms such as non-homologous end joining are invoked, leading to genomic instability (Karran, 2000. Curr Opin Genet Dev 10: 144-50; Khanna and Jackson, 2001. Nat Genet 27: 247-54; van Gent et al., 2001. Nat Rev Genet 2: 196-206). This instability is thought to predispose to familial breast and / or ovarian cancer in patients carrying germ line mutations in BRCA1 or BRCA2, genes involved in homologous recombination. Absence of homologous recombination offers a potential ...

Claims

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Application Information

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IPC IPC(8): C12Q1/68
CPCC12Q1/6886C12Q2600/154C12Q2600/158C12Q2600/118C12Q2600/106
Inventor LINN, SABINESEVERSON, TESAPEETERS, JUSTINE KATESIMON, IRIS
Owner STICHTING HET NEDERLANDS KANKER INST ANTONI VAN LEEUWENHOEK ZIEKENHUIS
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